This invention concerns the use of lactam derivatives as pharmaceutical compounds, new lactam derivatives as well as processes for their preparation.
Excessive formation of cytokines such as tumor necrosis factor a (TNF-xcex1), interleukin-2 (IL-2) and xcex3-interferon (IFN-xcex3), are pivotal in the pathogenesis of the Graft-versus-Host-Syndrome, transplant rejection and other immunologically triggered diseases such as Morbus Behcet, aphthous stomatitis, erythema nodosum leprosum, Morbus Boeck, cutaneous lupus erythematodes and rheumatoid arthritis. Modulation of cytokine release, e. g. using cyclosporin A or glucocorticoids, is a therapeutical option in these pathological situations. The problem of therapy by immunosuppressants, however, is that blockade of the immune system entails opportunistic infections, e.g. by fungi or viruses. Therefore, compounds which only partly suppress cellular immune reactions promise improvements of therapy. At present, no satisfactory compounds are available for this purpose. Thus, there has remained a need for further immunomodulating substances.
Thalidomide has been used since the late 1960""s in the treatment of erythema nodosum leprosum and several other disease entities such as Morbus Behcet, Lupus erythematodes, stomatitis aphthosa and Graft-versus-Host-Syndrome [The Lancet 1988, 117; N. Engl. J. Med. 326, 1055 (1992); Eur. J. Dermatol. 4, 9 (1994)]. During treatment with thalidomide there is no impairment of immunocompetence, and during all these years no association of thalidomide therapy with opportunistic infections has been reported. These findings correspond to experimental data where thalidomide, in contrast to typical immunosuppressants, does not reduce the release of cytokines TNF-xcex1, IL-2 and IFN-xcex3 below detection limits. Furthermore, and also in contrast to cyclosporin A and dexamethasone, thalidomide has not been reported to inhibit the proliferation of immunocompetent lymphocytes.
It has now been found that certain lactam derivatives have similar or superior activity compared to thalidomide in certain pharmacological models while not being teratogenic.
Accordingly, the present invention relates to the use of a lactam derivative of formula I 
in which X is CH2, S or Se and R is a C1-6-alkyl or the benzyl group and wherein Z and Zxe2x80x2 are different and denote CH2 or CO or Z and Zxe2x80x2 are both CO, in racemic or optically active form as a pharmaceutical agent.
The lactam derivatives of formula I, in particular those lactam derivatives of formula I in which R is a C1-3-alkyl group, i.e. a methyl-, ethyl-, propyl- or isopropyl group, are broadly immunomodulatory, especially immunosuppressive. Therefore the lactam derivatives of formula I are preferably used as immunomodulatory and/or immunosuppressive therapeutic agents.
Furthermore, lactam derivatives of formula I are especially suitable to reduce neoangiogenesis. Neoangiogenesis, i.e. the pathological formation of new blood vessels, is an undesirable reaction associated with immunological diseases such as Morbus Crohn and infections with mycobacterium leprae [Int. J. Leprosy 9, 193 (1941)] and granulomatous diseases.
In order to treat diseases of the immune system, such as Graft-versus-Host-disease, graft rejection, Morbus Behcet, Lupus erythematodes, autoimmune consequences of chronic infections, Morbus Crohn or Kawasaki syndrome lactam derivatives of formula I may be administered orally, intravenously, intraperitoneally, intradermally or intramuscularly, intranasally as well as topically, e.g. in the case of infections of the skin, the mucous membranes or the eyes. The amount dispensed to patients varies according to the weight of these patients and the route of administration, the indication and the severity of disease. Usually 1 to 10 mg/kg of a lactam derivative of formula I are administered.
Examples of suitable preparations for oral administration include tablets, sugar-coated tablets, capsules, granulates, drops, syrups and suspensions, for parenteral, topical or inhalatory administration solutions, suspensions, easily reconstituted dry preparations as well as sprays. Lactam derivatives of formula I may also be administered cutaneously in a depot in soluble form or by a patch, if necessary with additives that enhance penetration through the skin. Orally or cutaneously administerable formulations of these lactam derivatives can have the property of prolonged or sustained release.
All the above-mentioned types of pharmaceutical preparations are known per se and, since the lactam compounds according to the invention are chemically stable, incorporating them into these formulations is within the skill of a skilled pharmaceutical chemist. In the preparation of pharmaceuticals the appropriate care must be taken when choosing excipients, e.g. vehicles, fillers, solvents, diluents, coloring agents, flavoring agents, binders and disintegrants, and, in particular when preparing parenterally administrable preparations stability and isotonicity of liquid formulations has to be ensured.
Further the present invention relates to hitherto unknown lactam derivatives of formula I 
wherein X is CH2, S, or Se and R is a C1-6-alkyl- or the benzyl group, Z and Zxe2x80x2 are different and denote CH2 or CO, or Z and Zxe2x80x2 are both CO with the proviso, that X is not S, when Z is CO and Zxe2x80x2 is CH2, in racemic or in optically active form.
The compounds of formula I according to the invention show configurational stability. Compounds of formula I in which R is a methyl, ethyl, propyl or isopropyl group are preferred.
Depending on the meaning of the variable X, different methods have to be used to prepare the lactam derivatives of formula I. The subject matter of the invention therefore also includes several processes for preparing the lactam compounds according to the invention.
One aspect of the invention is a process for preparing a lactam derivative of formula I 
wherein X is CH2 and R is a C1-6-alkyl group or the benzyl group, Z and Zxe2x80x2 are different and denote CH2 or CO, or Z and Zxe2x80x2 are both CO, characterized in that a compound of formula II 
is reduced with zinc, lithium aluminum hydride or a complex borohydride at a temperature between +20xc2x0 C. and +100xc2x0 C.
Preferably the reaction is performed in a solvent. Suitable solvents include aliphatic carboxylic acids with 1 to 6 carbon atoms, for example formic acid, ethanoic acid, propanoic acid, butanoic acid, pentanoic acid, hexanoic acid, or mixtures of these acids, and/or aliphatic ethers, for example diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or mixtures of such ethers.
Examples of suitable complex borohydrides include the borane/tetrahydrofuran complex, lithium triethyl borohydride and lithium diisopropylamino borohydride.
Compounds of formula II can be obtained in a known manner by reaction of compounds of formula V 
with phthalic anhydrides, followed by an oxidation reaction.
The invention also relates to a process for preparing a lactam derivative of formula I 
wherein X is CH2 and R is a C1-6-alkyl group or the benzyl group, Z and Zxe2x80x2 are different and denote CH2 or CO, or Z and Zxe2x80x2 are both CO, characterized in that a compound of formula 
is reacted with a basic compound and subsequently with a C1-6-alkyl halide or a benzyl halide.
The reaction of a compound of formula III, which compounds are accessible via a method described in Acta Pharmaceutica Suecica 9, 431 (1972), with a basic compound, for example methyllithium, butyllithium, 1,1,1,3,3,3-hexamethyl disilazane, lithium diisopropylamide, or an alkali alcoholate, is preferably performed in anhydrous solvents, especially in aliphatic or cyclic ethers, for example diethyl ether, diisopropyl ether, tetrahydrofuran, and/or dioxane at a temperature between xe2x88x9278xc2x0 C. and 0xc2x0 C. The following alkylation with a C1-6-alkyl halide or a benzyl halide, especially with a C1-3-alkyl chloride, -bromide, or -iodide is preferably performed at temperatures between xe2x88x9230xc2x0 C. and +20xc2x0 C.
The invention additionally relates to a process for preparing a lactam derivative of formula I 
wherein X is S or Se, and R is a C1-6-alkyl group or the benzyl group, Z and Zxe2x80x2 are different and denote CH2 or CO, or Z and Zxe2x80x2 are both CO, with the proviso, that X is not S, when Z is CO and Zxe2x80x2 is CH2, characterized in that a compound of formula IV 
wherein Hal and Halxe2x80x2 have the same or different meanings and represent a chlorine or bromine atom, is reacted with a compound of formula V 
in the presence of a base at a temperature between xe2x88x9220xc2x0 C. and +50xc2x0 C.
Preferably a compound of formula IV in which Hal and Halxe2x80x2 represent chlorine atoms is reacted in the presence of a solvent, for example N,N-dimethylformamide, and a base, for example triethylamine, pyridine and/or diisopropyl ethyl amine. Compounds of formula IV can be prepared by a process described in published European Patent Application Nos. EP 54,672 and EP 354,412.
Compounds of formula VI 
are accessible via a process which is described in EP 54,672.